The WNT gene encodes a large family of secreted protein growth factors. During development, Wnt plays different roles in controlling cell fate, proliferation, migration, polarity, and death. In adults, WNT plays an important role in maintaining homeostasis, and abnormal activation of the WNT pathway is associated with various cancers.
WNT ligands signal through the Frizzled family of 7-transmembrane receptors and recently discovered LRP5 (lipoprotein receptor-related protein-5) and LRP6 (lipoprotein receptor-related protein-6) coreceptors. Structurally, Frizzled receptors have an extracellular Wnt binding domain, seven transmembrane regions, and an intracellular C-terminal tail.
Wnt signaling is transmitted through at least three different intracellular pathways, including the classical Wnt/β-catenin pathway, the "non-canonical" Wnt/Ca2+ pathway, and the Wnt/PCP (planar cell polarity) pathway. The Wnt/β-catenin pathway mainly regulates cell fate during development, while the Wnt/PCP pathway's primary function is to regulate cell cytoskeleton organization.
The WNT/β-catenin pathway is activated by WNT1, WNT3, WNT3a, WNT7a, and WNT8 and is involved in transformation. WNT signaling can prevent apoptosis by upregulating anti-apoptotic proteins like Survivin and stimulate angiogenesis by upregulating vascular endothelial growth factor (VEGF). The classical WNT signaling pathway also regulates the NRSF/REST and ENC1 (ectodermal-neocortical (with BTB-like domain)-1) genes to control stem cells. Wnt signaling is also inhibited by the secreted protein Dkk1, which inhibits Wnt signaling by binding to LRP5/6 and counteracting LRP5/6. Krm2 forms a ternary complex with Dkk1 and LRP6, inducing rapid internalization and removal of LRP6 from the plasma membrane.
The non-canonical Wnt signaling pathway, also known as the non-canonical Wnt-Frizzled signaling pathway, consists of two intracellular cascades, the Wnt/Ca2+ pathway, and the Wnt/PCP pathway. In the WNT/Ca2+ pathway, WNT proteins composed mainly of WNT1, WNT5A, and WNT11 bind to the cell surface Frizzled transmembrane receptors and participate in several cellular processes, stimulating nuclear factor NFAT and other transcription factors like CREB. Therefore, the Wnt/Ca2+ pathway is likely a G-protein-dependent signaling pathway.
In the Wnt/PCP pathway, Wnt proteins bind to the cell surface Frizzled transmembrane receptors and then activate Rho/Rac small GTPases and JNK through Dsh, subsequently assisting in the regulation of cell cytoskeleton organization and gene expression.
